Interleukin-17 in inflammatory skin disorders

PURPOSE OF REVIEW: Recently, a novel and unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from Th1 and Th2 cells, was discovered. The question is addressed as to what extent inflammatory skin diseases are associated with the actions of this newly discovered Th17 cell subset. RECENT FINDINGS: Th17 cells are involved in protection against bacterial pathogens. In addition, it is now clear that Th17 cells may also be crucial in the pathogenesis of various chronic inflammatory diseases that were formerly categorized as Th1-mediated disorders. SUMMARY: In this review, we summarize the current knowledge of IL-17 and Th17 cells and discuss the possible role of IL-17 in the pathology of psoriasis, contact hypersensitivity and atopic dermatitis. Whereas IL-17 may play an important role in the pathogenesis of psoriasis and contact hypersensitivity, its role in atopic dermatitis is still unclea

New roles for CD14 and IL-beta linking inflammatory dendritic cells to IL-17 production in memory CD4(+) T cells

Interleukin (IL)-1β has proven to be crucial in the differentiation of human and mouse Th17 cells. Although it has become evident that IL-1β has potent IL-17-inducing effects on CD4(+) T cells directly, it has not yet been explored whether IL-1β can also prime dendritic cells (DCs) for a Th17 instruction program. Here, we show that human immature DCs exposed to IL-1β promote IL-17 production in human memory CD4(+) T cells. IL-1β-primed DCs express high levels of CD14 that mediate IL-17 production through direct interaction with T cells. Moreover, culturing human CD4(+)CD45RO(+) memory T cells with soluble CD14 is sufficient for the upregulation of retinoic acid-related orphan receptor-γ thymus and IL-17 production. In addition, in a human in situ model using tissue-resident skin DCs, upregulation of CD14 expression induced by IL-1β on skin residents DCs promotes IL-17 production in memory T cells; strongly suggesting the in vivo relevance of this mechanism. Our findings uncover new roles for IL-1β and CD14, and may therefore have important consequences for the development of new therapies for Th17-mediated autoimmune diseases and bacterial and fungal pathogenic infection

Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells

How the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed human DCs to promote IL-17 production in memory Th cells through the nucleotide oligomerization domain 2 (NOD2)-ligand muramyldipeptide (MDP), a derivative of bacterial peptidoglycan. MDP enhanced obligate bacterial Toll-like receptor (TLR) agonist induction of IL-23 and IL-1, which promoted IL-17 expression in T cells. The role of NOD2 in this IL-23-IL-1-IL-17 axis could be confirmed in NOD2-deficient DCs, such as DCs from selected Crohn's disease patients. Thus, antibacterial Th17-mediated immunity in humans is orchestrated by DCs upon sensing bacterial NOD2-ligand MD

Muramyl dipeptide-induced differential gene expression in NOD2 mutant and wild-type Crohn's disease patient-derived dendritic cells

BACKGROUND: Mutations in the gene encoding the nucleotide-binding oligomerization domain 2 (NOD2) protein are associated with Crohn's disease (CD), but the mechanism underlying this is not completely understood. To study the mechanism of CD resulting from NOD2 mutations, we analyzed NOD2-dependent whole-genome expression profiles of patient-derived antigen-presenting cells. PATIENTS AND METHODS: Monocyte-derived dendritic cells (DCs) from CD carriers of double-dose NOD2 mutations, wild-type CD patients, and wild-type healthy volunteers were stimulated with the NOD2 ligand muramyl dipeptide. Whole-genome microarrays were used to assess the differential gene expression. The clustering of significantly changed genes was analyzed by online gene ontology mapping software. RESULTS: In the DCs from the wild-type CD patient group, 683 genes were significantly changed, with most of the genes clustering in the pathways of inflammatory response. In addition, a significant number of genes clustered in the apoptosis regulation-related pathway. In the DCs from the healthy volunteer group, only 50 genes were significantly changed, predominantly those belonging to the response to pathogen pathway. Analysis of differentially expressed gene ontology pathways in the DCs from the NOD2 mutant CD patient group showed that the transcription of pathogen response genes was absent. In this group, 298 genes were significantly changed, predominantly clustering in the negative apoptosis regulation and cell organization and biogenesis pathways. CONCLUSIONS: Our results suggest that NOD2 mutations may result in perpetuation of mucosal inflammation through insufficient pathogen elimination. Further, these observations implicate a possible role of defective regulation of dendritic cell apoptosis in CD pathogenesi

In-situ delivery of antigen to DC-SIGN+CD14+ dermal dendritic cells results in enhanced CD8+ T cell responses

CD14+ dendritic cells (DCs) present in the dermis of human skin represent a large subset of dermal DCs (dDCs) that are considered macrophage-like cells with poor antigen (cross)-presenting capacity and limited migratory potential to the lymph nodes. CD14+ dDC highly express DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), a receptor containing potent endocytic capacity, facilitating intracellular routing of antigens to major histocompatibility complex I and II (MHC-I andII) loading compartments for the presentation to antigen-specific CD8+ and CD4+ T cells. Here we show using a human skin explant model that the in situ targeting of antigens to DC-SIGN using glycan-modified liposomes enhances the antigen-presenting capacity of CD14+ dDCs. Intradermal vaccination of liposomes modified with the DC-SIGN-targeting glycan LewisX, containing melanoma antigens (MART-1 or Gp100), accumulated in CD14+ dDCs and resulted in enhanced Gp100- or MART-1-specific CD8+ T-cell responses. Simultaneous intradermal injection of the cytokines GM-CSF and IL-4 as adjuvant enhanced the migration of the skin DCs and increased the expression of DC-SIGN on the CD14+ and CD1a+ dDCs. These data demonstrate that human CD14+ dDCs exhibit potent cross-presenting capacity when targeted in situ through DC-SIGN

In situ Delivery of Antigen to DC-SIGN + CD14 + Dermal Dendritic Cells Results in Enhanced CD8 + T-Cell Responses

CD14 + dendritic cells (DCs) present in the dermis of human skin represent a large subset of dermal DCs (dDCs) that are considered macrophage-like cells with poor antigen (cross)-presenting capacity and limited migratory potential to the lymph nodes. CD14 + dDC highly express DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), a receptor containing potent endocytic capacity, facilitating intracellular routing of antigens to major histocompatibility complex I and II (MHC-I andII) loading compartments for the presentation to antigen-specific CD8 + and CD4 + T cells. Here we show using a human skin explant model that the in situ targeting of antigens to DC-SIGN using glycan-modified liposomes enhances the antigen-presenting capacity of CD14 + dDCs. Intradermal vaccination of liposomes modified with the DC-SIGN-targeting glycan Lewis X, containing melanoma antigens (MART-1 or Gp100), accumulated in CD14 + dDCs and resulted in enhanced Gp100- or MART-1-specific CD8 + T-cell responses. Simultaneous intradermal injection of the cytokines GM-CSF and IL-4 as adjuvant enhanced the migration of the skin DCs and increased the expression of DC-SIGN on the CD14 + and CD1a + dDCs. These data demonstrate that human CD14 + dDCs exhibit potent cross-presenting capacity when targeted in situ through DC-SIGN